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PubMed1978

[Haematuria in children. I. Differential diagnosis of haematuria in childhood (author's transl)].

Haematuria in children is either of glomerular or nonglomerular origin. In the latter case intravenous urography should always be performed. A renal biopsy is indicated if unexplained haematuria persists for at least one year or if an unfavorable prognosis is indicated by the appearance of hypertension, significant proteinuria or persistently low levels of serum complement (C3). The importance of screening the families of haematuric patients is emphasized. More than half of our cases with persistent or intermittent haematuria undergoing renal biopsy showed no or only minimal glomerular changes. In other children with a similar clinical picture more severe histological lesions were detected. In any case the kidney tissue obtained by biopsy should be examined by immunofluorescence and by electron microscopy. One of the most frequent causes for persistent or intermittent haematuria during childhood is Berger's disease (IgA/IgG nephropathy).

Adolescent↗
PubMed1983

[Severe visceral necrotizing angiitis with hereditary immune disorders: a case].

The authors report a new case of necrosing angeitis similar to those individualised by Churg and Strauss in 1951. After a persistent rhinitis, the patient developed serious asthma, left hemiplegia 8 months later (secondary to an intracerebral hemorrhage) polyneuritis and extensive necrosis of the small intestine. There was no renal or cardiac involvement. Anatomopathological examination of the small intestine revealed an arteriolitis with periarterial granuloma and severe inflammation. Complementary investigations revealed a hypereosinophilia, an inflammatory syndrome, a reduction in the hemolytic 50 complement and of the C4 fraction. Corticosteroid therapy associated with cyclophosphamide formed the basis of treatment. Plasmapheresis have been a useful aid. The follow-up is too short to assess the long term prognosis. A familial immune deficiency, disseminated lupus erythematosis in a sister, and rheumatoid purpura in one of the patient's children are interesting features of this text.

Adult↗
PubMed1976

Hereditary C2 deficiency: diagnosis and HLA gene complex associations.

Nine families with genetically controlled C2 deficiency have been described where the propositii and family members are heterozygous C2 deficient. The diagnosis of hereditary C2 heterozygous deficiency was suspected on the basis of analysis for CH50, C2 protein, and C2 function, and then confirmed by family studies. Analysis of HLA antigens in these families supported the close association of C2 defiency and HLA-A10 and/or B18, particularly the latter. Analysis by MLC studies revealed recombination in one family between the HLA and B and D loci and in another family probable recombination between the D and C2 complement loci. Therefore, the order of the loci on the sixth chromosome is likely to be C2 complement, HLA-D, HLA-B, HLA-A.

Chromosome Mapping↗
PubMed1987

Restriction fragment length polymorphism of the C1 inhibitor gene in hereditary angioneurotic edema.

Hereditary angioneurotic edema (HANE) results from the deficiency of the inhibitor of the first component of human complement (C1-INH). It is inherited as an autosomal dominant trait. Heterogeneity of this defect has been shown at the protein and mRNA level. Southern blot analysis of genomic DNA was performed after digestion with six different restriction endonucleases in 24 families affected with type 1 HANE (low antigenic and functional C1-INH levels) and five with type 2 (low functional C1-INH levels and normal or elevated levels of dysmorphic C1-INH). Blots were hybridized with a C1-INH cDNA probe of 1,227 bp. With one enzyme (Pst I), two different patterns of restriction fragment length polymorphism (RFLP) were detected. One was present in one kindred with type 1 HANE and the other appeared the same in one type 1 and in one type 2 family, thus indicating that each RFLP resulted from a different mutation. Analysis of a total of 34 members of these three families suggested that the polymorphisms are tightly linked to the mutation responsible for the disease. Using a 170-bp probe we showed that the three different mutations leading to these polymorphisms are located in the same region of the C1-INH gene. These data suggest that different mutations in the same region of the C1-INH gene are responsible for C1-INH deficiency in these families. Most of these mutations are probably point mutations or other "minor" defects and do not appear to be due to major deletions or rearrangements.

Angioedema↗
PubMed2000

[Immunology in the medical practice. XXVII. Mannose-binding lectin, an important link for nonspecific or hereditary immune reaction].

In the course of the past two decennia, a 3rd route of complement activation (next to the classical and the alternative routes) has been identified: the lectin route in which mannose-binding lectin (MBL) plays an essential role. MBL is produced in the liver. From the phylogenetic and functional points of view, complement activation via MBL falls in between the alternative and the classical routes and combines the advantages of the former (an early response, without the intervention of antibodies) with those of the latter (high specificity). The binding of MBL to the surface of a microorganism results in the activation of two serine proteases (MASP1 and MASP2) that are coupled to MBL. These enzymes can activate C4 and C2 so that, via the MBL route, the C3-convertase of the classical route (C4b2b) is produced long before there are any specific antibodies. The gene for MBL is located on the long arm of chromosome 10 and consists of a promoter gene and 4 exons coding for the protein. The prevalence of mutations in the MBL gene is about 10%, but in Africa South of the Sahara it is as high as 30%. MBL deficiency predisposes both children and adults to all sorts of infectious diseases, chronic diarrhoea, tonsillitis, otitis media, pneumonia, (meningococcal) meningitis, sepsis and osteomyelitis. Remarkably, MBL deficiency may actually be advantageous in some infections, because certain microorganisms use MBL or complement to invade the cell.

Carrier Proteins↗
PubMed2003

The transcriptional response after oxidative stress is defective in Cockayne syndrome group B cells.

Cockayne syndrome (CS) is a human hereditary disease belonging to the group of segmental progerias, and the clinical phenotype is characterized by postnatal growth failure, neurological dysfunction, cachetic dwarfism, photosensitivity, sensorineural hearing loss, and retinal degradation. CS-B cells are defective in transcription-coupled DNA repair, base excision repair, transcription, and chromatin structural organization. Using array analysis, we have examined the expression profile in CS complementation group B (CS-B) fibroblasts after exposure to oxidative stress (H2O2) before and after complete complementation with the CSB gene. The following isogenic cell lines were compared: CS-B cells (CS-B null), CS-B cells complemented with wild-type CSB (CS-B wt), and a stably transformed cell line with a point mutation in the ATPase domain of CSB (CS-B ATPase mutant). In the wt rescued cells, we detected significant induction (two-fold) of 112 genes out of the 6912 analysed. The patterns suggested an induction or upregulation of genes involved in several DNA metabolic processes including DNA repair, transcription, and signal transduction. In both CS-B mutant cell lines, we found a general deficiency in transcription after oxidative stress, suggesting that the CSB protein influenced the regulation of transcription of certain genes. Of the 6912 genes, 122 were differentially regulated by more than two-fold. Evidently, the ATPase function of CSB is biologically important as the deficiencies seen in the ATPase mutant cells are very similar to those observed in the CS-B-null cells. Some major defects are in the transcription of genes involved in DNA repair, signal transduction, and ribosomal functions.

Adenosine Triphosphatases↗
PubMed2004

Update on human systemic lupus erythematosus genetics.

PURPOSE OF REVIEW: Susceptibility to systemic lupus erythematosus (SLE) has a genetic component. In recent years, nine complete genome scans using family collections that differ greatly in ethnic compositions and geographic locations have identified several strong, confirmed SLE susceptibility loci. Evidence implicating individual gene polymorphisms (or haplotypes) within some of the linked intervals has been reported. This review highlights recent findings that may lead to the identification of putative genes and new insights in the pathogenesis of SLE. RECENT FINDINGS: Eight of the best-supported SLE susceptibility loci are 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12p24, and 16q12. These are chromosomal regions exhibiting genome-wide significance for linkage in single studies and suggestive evidence for linkage in other samples. Linkage analyses conditioning on pedigrees in which one affected member manifesting a particular clinical condition have also yielded many chromosomal regions linked to SLE. The linked interval on chromosome 6p has been narrowed to 0.5 approximately 1.0 Mb (million basepairs) of 3 MHC class II containing risk haplotypes in white subjects. Cumulative results have shown that hereditary deficiencies of complement component C4A (a MHC class III gene) confer risk for SLE in almost all ethnic groups studied. The FcgammaR genes (located at 1q23) have been convincingly demonstrated to play an important role in susceptibility to SLE (and/or lupus nephritis). The evidence for the intronic single nucleotide polymorphism of program cell death gene 1 (PDCD1 at 2q37) to confer susceptibility is promising but not yet compelling. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. SUMMARY: Further replications of linkage and association are the immediate task. The respective contribution of each susceptibility gene, relationships between genotypes and phenotypes, and potential interactions between susceptibility gene products need to be elucidated. This line of investigation is now well poised to provide novel insights into how genetic variants can affect functional pathways leading to the development of SLE.

Genetic Predisposition to Disease↗
PubMed1996

Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family.

Two siblings (case 1 and case 2) with homozygous C1q deficiency are described. Both presented with a photosensitive rash, and during follow-up case one developed SLE with nephrotic range proteinuria. Case 2 had microscopic hematuria with a past history of macroscopic hematuria. Renal biopsies revealed mesangioproliferative glomerulonephritis in case 1 and IgA nephropathy in case 2, a new finding in association with C1q deficiency. Since the classical pathway of complement plays a role in the development of antibody responses, the family was also evaluated for the immune response to hepatitis B vaccine. Antibody response to hepatitis B vaccine was normal in both affected members and the rest of the family. The A-, B- and C- chain genes of C1q were amplified by PCR and directly sequenced. A homozygous C to T point mutation was identified in genomic DNA isolated from the patients at codon 186 in the A chain that resulted in a premature stop codon. This mutation was present in both parents and both unaffected sibs in the heterozygous state. This mutation was identical to that previously described in a Slovakian family with C1q deficiency. Because of this finding, a series of 92 genomic DNA samples was screened from ethnically distinct patient groups with SLE to test the hypothesis that this mutation of C1q may be a widespread disease susceptibility gene. No further examples of this mutation were found.

Adolescent↗
PubMed1992

Recurrent venous thrombosis during warfarin treatment related to acquired protein S deficiency.

Failure of warfarin to prevent new thrombotic processes was observed in three patients with very low free protein S concentrations and high C4b-binding protein (C4bBP) concentrations, and in one patient with hereditary protein S deficiency. We suggest that an increase in C4bBP reduces the free Protein S level, and warfarin treatment causes an additional decrease of free protein S. The four patients presented indicate that such reductions are of clinical importance. Heparin seems preferable as an anticoagulant in this situation, as warfarin given alone is ineffective, or may even be harmful. In a group of pancreatic cancer patients with advanced disease, subnormal mean free protein S was found, whereas mean total protein S concentration, and mean C4bBP concentrations were significantly higher (p less than 0.01) than in healthy controls. These findings indicate that an increase in C4bBP may induce free protein S deficiency contributing to the increased thrombotic tendency in this group of patients. The correlation between free protein S and C4bBP was 0.11, (n.s.), between total protein S and C4bBP 0.73 (p less than 0.0001).

Adult↗
PubMed2006

Hereditary angio-oedema with normal C1 inhibitor in a family with affected women and men.

Recurrent angio-oedema is a sign of various acquired and inherited disease entities, including hereditary angio-oedema types I and II that result from a genetic deficiency of C1 inhibitor, and a recently described type of dominantly inherited angio-oedema, which does not show a deficiency of C1 inhibitor. Until now, this new type of hereditary angio-oedema, designated as hereditary angio-oedema type III, has been assumed to be a disorder specific to females. We now describe a four-generation family with dominantly inherited angio-oedema and normal C1 inhibitor in which, in contrast to all previous observations, not only five female but also three male family members were clinically affected. One male patient was mainly affected following the intake of angiotensin-converting enzyme inhibitors. Our current observation leads to new considerations about the classification of hereditary angio-oedema with normal C1 inhibitor. Either hereditary angio-oedema with normal C1 inhibitor can be an entity affecting females predominantly, but not exclusively; in that case, men appear to have a much reduced chance of clinical manifestations. Alternatively, our present observation of hereditary angio-oedema with normal C1 inhibitor affecting both sexes may represent a new disease entity, presumably with a different underlying defect.

Adult↗
PubMed1992

Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis.

OBJECTIVE: We describe a dysfunction of C3 in a patient with a systemic lupus erythematosus (SLE)-like syndrome. Alternative pathway complement function was absent, but classical pathway complement function was partially intact. METHODS: We used functional, preparative, and immunochemical techniques in the study. RESULTS: The patient's C3 proved normally susceptible to trypsin proteolysis and partially resistant to classical pathway, but completely resistant to alternative pathway, convertase-dependent cleavage. CONCLUSION: The dysfunction, thus, was caused by a failure of C3 to interact with the C3 convertases, rather than by a lack of a proteinase-sensitive cleavage site in the deficient protein.

Adult↗
PubMed2004

Current advances in the human lupus genetics.

Genetic predisposition has been firmly established as a key element in susceptibility to systemic lupus erythematosus (SLE). During the past three decades, association studies have assessed many genes for potential roles in predisposing to SLE. These studies have identified a few risk factors including hereditary deficiency of complement components, major histocompatibility complex class II alleles, and allelic variants for the Fc portion of IgG (FCGR) genes. In recent years, a few groups have completed linkage analyses in data sets from families containing multiple members affected with SLE. Results from these initial genome scans are encouraging; approximately eight chromosomal regions have been identified exhibiting evidence for significant linkage to SLE and have been confirmed using independent cohorts (1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p11-21, 12q24, and 16q12), suggesting the high likelihood of the presence of one or multiple SLE susceptibility genes at each locus. Another approach of linkage analyses conditioned on pedigrees where one affected member manifesting a particular clinical condition has also identified many chromosomal regions linked to SLE. Within several established susceptibility loci, evidence for association of positional candidate genes is emerging. Within 2q35-37, an intronic single nucleotide polymorphism (SNP) of the positional candidate gene program cell death 1 gene has been associated with SLE susceptibility. The SLE-associated SNP affects a transcription factor, RUNX1, binding site. Recently, SNPs of novel positional candidate genes that influence RUNX1 binding motifs have also been associated with other autoimmune diseases, suggesting the possibility of a common theme shared among susceptibility genes for autoimmune diseases. In the coming years, susceptibility genes responsible for the observed linkage will be identified, and will lead to further delineating genetic pathways involved in susceptibility to SLE.

Animals↗
PubMed1992

Molecular bases for hereditary cancer-prone diseases.

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Management of a patient with hereditary angioneurotic edema.

Patients with a history of hereditary angioneurotic edema can adequate and safely have nonelective surgical procedures performed with proper preoperative and postoperative management. Deficient amounts of C1 esterase inhibitor can be replaced with fresh frozen plasma; capillary permeability and spreading edema can be prevented with antifibrinolytic agents such as Amicar. Once edema has occurred peripherally and no laryngeal symptoms are present, conservative treatment is advisable. When epiglottic and laryngeal edema occurs, intubation or tracheostomy is preferred for maintenance of airway until the edema subsides. During oral surgical procedures, minimal surgical trauma must be achieved. Edema that involves the airway presents the greatest danger to patients. These attacks are usually associated with dental or some sort of oral or pharyngeal manipulation.

Angioedema↗
PubMed1982

Chemotactic factor inactivation by stimulated human neutrophils mediated by myeloperoxidase-catalyzed methionine oxidation.

Leukocyte chemoattractants were inactivated when exposed to human neutrophils and either ingestible particles or phorbol esters. Loss of biologic activity was time- and temperature-dependent, required physiologic concentrations of viable neutrophils and a halide, and was inhibited by azide or catalase. Neutrophils from patients with either hereditary myeloperoxidase deficiency or chronic granulomatous disease failed to inactivate the chemoattractants unless purified myeloperoxidase or H2O2, respectively, was added. Susceptibility to inactivation by neutrophils correlated with the presence of methionine in the attractant. Loss of chemotactic activity was blocked by low concentrations of methionine and by higher concentrations of other reducing agents, but was unaffected by oxidized methionine. Paper chromatography demonstrated that exposure of a formyl-methionyl peptide chemotactic factor to either the cellfree myeloperoxidase system or stimulated neutrophils resulted in its conversion to a molecular species whose location in the chromatographs was identical to that of the peptide containing oxidized methionine. Thus, stimulated human neutrophils inactivate peptide chemoattractants by secretion of myeloperoxidase and H2O2, which combine with halides to form oxidants that react with a critical methionine residue. We suggest that myeloperoxidase-catalyzed oxidation of thioethers may constitute an inflammatory control mechanism as well as a general means of modifying the functional properties of biologic mediators.

Aminopeptidases↗
PubMed1996

Mismatch repair and cancer.

A common form of human malignancy, hereditary non-polyposis colorectal cancer (HNPCC), as well as some sporadic human cancers, has been shown to exhibit frequent alterations in microsatellite sequences. This phenotype was ascribed to a defect in replication error correction, and indeed several tumour derived cell lines are deficient in mismatch repair. To date, four HNPCC loci, on chromosomes 2p, 2q, 3p and 7q, have been linked with genes designated hMSH2, hPMS1, hMLH1 and hPMS2, respectively, which encode proteins that display an extensive degree of sequence similarity to polypeptides involved in postreplicative mismatch correction in Escherichia coli and Saccharomyces cerevisiae. We have recently identified a new protein, GTBP, that is essential for mismatch repair in human cells. GTBP mutations are not associated with the profound MI commonly encountered in hereditary colon cancers. The roles of the proteins encoded by the individual mismatch repair genes in postreplicative mismatch correction and genome instability are discussed, with a view to assessing the potential utility of these findings in diagnosis of cancer predisposition and therapy.

Adenosine Triphosphatases↗
PubMed1992

The C1 inhibitor deficiency. A review.

C1 inhibitor (C1I), a member of the serine protease inhibitor superfamily, is the principal regulator of the activation classical pathway of complement by reducing the proteolytic activity of activated C1r and C1s. A deficiency of active C1 inhibitor is the most commonly identified genetic defect of the complement system. It is associated with a pathology called angioedema. There are three forms of hereditary angioedema. The first type is characterized by an insufficient production of a normal protein. The two other forms are characterized by the presence of an abnormal C1 inhibitor protein. Moreover a reduction of functional C1 inhibitor may also be acquired. There are two types of acquired angioedema, a form associated with malignancy (B cell lineage, breast cancer, ...) and an autoimmune form. Angioedema manifests itself by attacks of swelling of the extremities, face, trunk, airways, or abdominal viscera, occurring spontaneously or as a result of trauma. Three main categories of substances have been proposed for the treatment of C1 deficiencies: the androgens, the antifibrinolytics and fresh plasma or purified C1 inhibitor. To distinguish between the different forms of C1 inhibitor deficiencies, it is necessary to determine the amount of C1 inhibitor protein and the level of its functional activity. Several methods for the determination of C1 inhibitor have been proposed: titrimetric and spectrophotometric assays, inhibition of complement haemolytic activity, radioimmunoassay, enzyme-linked immunosorbent assay, ...), in order to improve the diagnosis and the treatment of angioedema.

Angioedema↗
PubMed1990

Autoimmune angioedema: a new role for autoantibody in disease pathogenesis.

Angioedema may be due to hereditary forms of Cl-Inh deficiency, but recently an autoimmune form of angioedema has been described in which the mechanism is novel. While the peripheral blood monocytes of patients with autoimmune angioedema produce a normal, functionally active, 105 KD Cl-Inh in normal quantities, the Cl-Inh isolated from the patient's plasma exists in a dysfunctional lower molecular weight (96 KD) performance. Rather than bind and biologically inactivate the enzyme, a relatively common phenomenon in autoimmune disease, the autoimmune angioedema cleave the Cl-Inh molecule. The following sequence of events is proposed: structural and functionally normal Cl-Inh is synthesised and secreted, this secreted inhibitor is complexed by autoantibody and following enzyme interaction, denatured 96 KD Cl-Inh is proposed. This process depletes the pool of normal, functional Cl-Inh to critical levels and predisposes patients to episodes of oedema.

Angioedema↗